The Wnt family of proteins are secreted signaling molecules that regulate a number of critical developmental processes, including cellular proliferation and differentiation. Moreover, aberrant activation of the Wnt signaling pathway has been shown to be an important component in oncogenesis. Wnt signaling is very complex and is initiated by a family of transmembrane heptahelical receptors known as Frizzled, which are most closely related to the family of G protein coupled-receptors. Despite evidence implicating G proteins in Wnt/Frizzled signal transduction, the precise mechanism by which Frizzled receptors choose downstream targets and transmit signals to them is still unclear. In this application, I propose to identify specific Frizzled/G protein interactions to test the hypothesis that Frizzled receptors are, in fact, G protein-coupled receptors. In addition, I will attempt to define the role of G proteins in determining Wnt/Frizzled signaling pathway choices and in linking Frizzled to known downstream target molecules such as Axin. The proposed project will be undertaken with the mentorship of Dr. Patrick J. Casey and Dr. Robert J. Lefkowitz and with the support of the Department of Pathology at Duke University. My background in protein biochemistry and G protein signaling provides a solid foundation for initiating these studies. This award will allow me to develop skills necessary to progress to the study of more biological aspects of cell regulation and will facilitate my transition to an independent investigator.